NO174258B - Analogous Process for Preparation of Therapeutically Active Crystalline Cephemic Acid Salts - Google Patents

Analogous Process for Preparation of Therapeutically Active Crystalline Cephemic Acid Salts Download PDF

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NO174258B
NO174258B NO902607A NO902607A NO174258B NO 174258 B NO174258 B NO 174258B NO 902607 A NO902607 A NO 902607A NO 902607 A NO902607 A NO 902607A NO 174258 B NO174258 B NO 174258B
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cephem
crystalline
preparation
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ester
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Fiedhelm Adam
Walter Duerckheimer
Burkhard Mencke
Dieter Isert
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Hoechst Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Crystalline cephem acid addition salts of the general formula II <IMAGE> pharmaceutical preparations active against bacterial infections and which contain such cephem derivatives, process for preparing the cephem derivatives and the pharmaceutical preparations, and use of the cephem derivatives for controlling bacterial infections.

Description

Gjenstand for oppfinnelsen er fremstillingen av krystallinske, enteralt resorberbare salter av 7-[2-(2-aminotiazol-4-yl)-2-(Z) hydroksyimino-acetatamido]-3-metoksymetyl-3-cefem-4-karboksylsyre-a-(2,2-dimetyl-propanoyloksy)-etylestere med formel I The object of the invention is the preparation of crystalline, enterally resorbable salts of 7-[2-(2-aminothiazol-4-yl)-2-(Z)hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid-a -(2,2-dimethyl-propanoyloxy)-ethyl esters of formula I

Mange klinisk relevante cefalosporiner med bredt anti-mikrobielt spektrum er allerede utviklet. De fleste egner seg imidlertid bare for en parenteral anvendelse, idet de etter oral tilførsel bare resorberes i .meget utilstrekkelig grad, om overhodet. I mange tilfeller er det imidlertid ønskelig å tilføre pasientene meget virksomme antibiotika i oral form. Denne formen for behandling er enklere og reduserer i betydelig grad behandlingskostnadene. Many clinically relevant cephalosporins with a broad antimicrobial spectrum have already been developed. However, most are only suitable for parenteral use, since after oral administration they are only absorbed to a very insufficient extent, if at all. In many cases, however, it is desirable to give the patients highly effective antibiotics in oral form. This form of treatment is simpler and significantly reduces treatment costs.

I noen tilfeller har det lykkes å forhøye resorpsjonen av et cefalosporin i gastrointestinalkanalen ved forestring av 4-karboksygruppen. Idet cefalosporinesteren som regel per se ikke oppviser noen antibiotisk virksomhet, må esterkompo-nentene velges slik at esteren etter resorpsjon ved kropps-egne enzymer, som esteraser, deretter raskt og fullstendig tilbakespaltes til cefalosporin méd frie karboksylgrupper. In some cases, it has been successful to increase the absorption of a cephalosporin in the gastrointestinal tract by esterification of the 4-carboxy group. As the cephalosporin ester usually does not per se show any antibiotic activity, the ester components must be chosen so that the ester, after resorption by the body's own enzymes, such as esterases, is then quickly and completely cleaved back to cephalosporin with free carboxyl groups.

I de tyske patentpublikasjoner P 38 04 841 og P 38 09 561 beskrives et antall estere av 7-[2-(2-aminotiazol-4-yl)-2-(Z )-hydroksyimino-acetamido] - 3 -me tok syrne ty 1 -3-cef em-4-karboksylsyre, som resorberes meget godt enteralt i forskjellige dyrespesis. Av de i den tyske patentpublikasjonen In the German patent publications P 38 04 841 and P 38 09 561, a number of esters of 7-[2-(2-aminothiazol-4-yl)-2-(Z )-hydroxyimino-acetamido]-3-me toc acids are described 1 -3-cef em-4-carboxylic acid, which is very well absorbed enterally in various animal species. Of those in the German patent publication

P 38 04 841 omtalte esterne, ble det funnet at esteren med formel I var av spesiell interesse. P 38 04 841 discussed the esters, it was found that the ester of formula I was of particular interest.

Denne esteren har et asymmetrisk karbonatom i 1-stilling av 1-pivaloygruppen og kan derfor eksistere i form av R- og S-isomerer eller blandinger derav. Fremgangsmåten for fremstilling av esteren med formel I, som er beskrevet i den tyske patentpublikasjonen P 38 04 841, gir materialet i amorf form. De to diastereomerene har den samme resorp-s j onen. This ester has an asymmetric carbon atom in the 1-position of the 1-pivaloy group and can therefore exist in the form of R- and S-isomers or mixtures thereof. The process for preparing the ester of formula I, which is described in the German patent publication P 38 04 841, gives the material in amorphous form. The two diastereomers have the same resorption zone.

Forsøk på krystallisasjon av I fra de vanlige organiske oppløsningsmidlene førte til tap. Dessuten forskyves forholdet mellom de to diastereomerene, som har forskjellige oppløseligheter, ved krystallisasjonstrinnet. Attempts at crystallization of I from the usual organic solvents led to losses. Moreover, the ratio between the two diastereomers, which have different solubilities, is shifted by the crystallization step.

Fremstillingen av et salt av I lykkes på grunn av den svake basisiteten for aminogruppen bare når man omsetter esteren med formel I med sterke syrer. De innen patent1 itteraturen og øvrig litteratur beskrevne fremgangsmåtene for fremstilling av krystallinske salter av de forskjellige cefalo-sporinesterne førte ikke til ønsket resultat ved anvendelse på den ovenfor nevnte forbindelsen. Følgelig fører for eksempel fremstillingen av et hydroklorid, sulfat eller fosfat bare til et amorft produkt. The preparation of a salt of I is successful due to the weak basicity of the amino group only when reacting the ester of formula I with strong acids. The methods for producing crystalline salts of the various cephalosporin esters described in the patent literature and other literature did not lead to the desired result when applied to the above-mentioned compound. Consequently, for example, the preparation of a hydrochloride, sulfate or phosphate only leads to an amorphous product.

Det var derfor overraskende at det ved oppfinnelsen ble oppnådd krystallinske produkter. It was therefore surprising that crystalline products were obtained by the invention.

Fremstillingen av en krystallinsk ester eller et krystallinsk salt, som inneholder begge isomerene i et tilnærmet forhold på 1:1, er imidlertid meget ønskelig. En slik operasjon fører til en forbedring av enheten, forbedret stabilitet for den labile e-laktam-esteren. Renheten kan bestemmes ved fysiokjemiske parametere som for eksempel høyt smeltepunkt, oppløselighet, stabilitet, isomerisering av dobbelt-bindingen. Dessuten er det på denne måten mulig, i tilfeller hvor oppløsningsmidler eller andre ved saltfremstillingen anvendte stoffer lagres inn i krystallgitteret eller absorberes, å oppnå produkter med definert og reproduserbar sammensetning. However, the production of a crystalline ester or a crystalline salt, which contains both isomers in an approximate ratio of 1:1, is highly desirable. Such an operation leads to an improvement of the unit, improved stability of the labile ε-lactam ester. The purity can be determined by physiochemical parameters such as high melting point, solubility, stability, isomerization of the double bond. Moreover, in this way it is possible, in cases where solvents or other substances used in salt production are stored in the crystal lattice or absorbed, to obtain products with a defined and reproducible composition.

Gjenstanden for oppfinnelsen er fremstillingen av krystallinske, støkiometriske og enteralt resorberbare salter med generell formel II The object of the invention is the preparation of crystalline, stoichiometric and enterally resorbable salts of general formula II

hvor R står for hydrogen eller C^-C^alkyl og gruppen =N-OH står i syn-posisjon. where R stands for hydrogen or C^-C^alkyl and the group =N-OH is in the syn position.

Dersom R har betydningen av C^-C^alkyl, så kan den stå for f.eks. metyl, etyl, propyl, isopropyl, butyl, isobutyl eller tert.-butyl. Foretrukket er for R betydningen hydrogen, metyl eller etyl, spesielt metyl eller etyl. R kan være orto-, meta- eller parastående, men fortrinnsvis parastående. Som foretrukne syreaddisjonssalter kommer følgende i betraktning: benzensulfonat, toluensulfonat eller p-etyl-benzosulfonat. If R has the meaning of C^-C^alkyl, then it can stand for e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. Preferred is for R the meaning hydrogen, methyl or ethyl, especially methyl or ethyl. R can be ortho-, meta- or para-position, but preferably para-position. As preferred acid addition salts, the following come into consideration: benzenesulfonate, toluenesulfonate or p-ethyl benzosulfonate.

Forbindelser med generell formel II fremstilles ifølge oppfinnelsen ved at man omsetter et amorft cefem med generell formel I Compounds of general formula II are prepared according to the invention by reacting an amorphous cephem of general formula I

med en syre med generell formel III with an acid of general formula III

hvori R står for hydrogen eller Ci-C4~alkyl, i et organisk oppløsningsmiddel og lar syreaddisjonssalt krystalliseres direkte eller ved tilsats av et annet organisk oppløsnings-middel eller av vann. in which R stands for hydrogen or C1-C4~alkyl, in an organic solvent and allows the acid addition salt to be crystallized directly or by the addition of another organic solvent or water.

Syrekomponentene kan anvendes i svakt overskudd, fortrinnsvis 1-1,5 ekvivalenter, relativt til esteren med formel I. The acid components can be used in slight excess, preferably 1-1.5 equivalents, relative to the ester of formula I.

Valget av oppløsningsmiddel har vist seg å være av be-tydning. For å oppnå et tilnærmet l:l-forhold mellom de to diastere- The choice of solvent has proven to be important. In order to achieve an approximate l:l ratio between the two diastere-

omerene må det velges et oppløsningsmiddelsystem som sikrer en praktisk talt kvantitativ utvinnelse av saltene. omers, a solvent system must be chosen that ensures a practically quantitative recovery of the salts.

For omsetningen kommer det på tale organiske oppløsnings-midler som ikke er blandbare med vann, som for eksempel eddikester, eddiksyre-n-butylester eller eddiksyre-tert.-butylester, fortrinnsvis imidlertid oppløsninger som, med tanke på en senere eventuelt påkrevet vanntilsats, er blandbare med vann. For the turnover, there are organic solvents that are not miscible with water, such as acetic ester, acetic acid n-butyl ester or acetic acid tert-butyl ester, preferably, however, solutions which, in view of a later possibly required addition of water, are miscible with water.

Som organiske oppløsningsmidler som er blandbare med vann, kommer for eksempel følgende i bétraktning: C^-C4-alkoholer, som for eksempel metanol, etanol, isopropanol, propanol, butanol , 2-butanol, isobutanol, tert.-butanol, aceton, tetrahydrofuran eller blandinger derav. Spesielt foretrukket er etanol, propanol og aceton. For fullførelse av krystallisasjonen kan det også tilsettes et med vann ikke blandbart oppløsningsmiddel, som eksempelvis n-heksan, toluen, dietyleter eller diisopropyleter til suspensjonen av krystaller i en blanding av vann og det med vann blandbare oppløsningsmidlet. En slik oppløsningsmiddeltilsats er naturligvis også mulig når omsetningen_gjennomføres i et med vann ikke blandbart organisk oppløsningsmiddel. As organic solvents which are miscible with water, for example, the following come into consideration: C^-C4 alcohols, such as methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, isobutanol, tert.-butanol, acetone, tetrahydrofuran or mixtures thereof. Particularly preferred are ethanol, propanol and acetone. To complete the crystallization, a water-immiscible solvent, such as n-hexane, toluene, diethyl ether or diisopropyl ether, can also be added to the suspension of crystals in a mixture of water and the water-miscible solvent. Such a solvent addition is of course also possible when the reaction is carried out in a water-immiscible organic solvent.

Ved den ifølge oppfinnelsen foretrukne vanntilsatsen utgjør mengden av det totalt tilsatte vannet eksempelvis inntil 20 ganger volumet av den organiske oppløsningen, det kan imidlertid også ligge vesentlig høyere. With the water addition preferred according to the invention, the amount of the total water added is, for example, up to 20 times the volume of the organic solution, but it can also be significantly higher.

Forenelsen av den organiske oppløsningen med vannet eller med et ytterligere organisk oppløsningsmiddel foregår langsomt, for eksempel dråpevis, i den grad at det oppnås en god krystallinitet for produktet. The combination of the organic solution with the water or with a further organic solvent takes place slowly, for example drop by drop, to the extent that a good crystallinity is achieved for the product.

Krystallisasjonen foregår fortrinnsvis ved romtemperatur. Men også ved temperaturer på eksempelvis 0 til 40°C oppnår man gode resultater. En etteromrøringstid på inntil ca. 3 timer eller mer, fullstendiggjør krystallisasjonen. The crystallization preferably takes place at room temperature. But good results are also achieved at temperatures of, for example, 0 to 40°C. A post-stirring time of up to approx. 3 hours or more, completes the crystallization.

De derved oppnådde krystallinske saltene med formel II adskilles ved vanlige laboratoriefremgangsmåter, som for eksempel filtrering, og befris under svakt vakuum for vedhengende oppløsningsmiddel. The crystalline salts of formula II thus obtained are separated by usual laboratory methods, such as filtration, and freed under a weak vacuum of any remaining solvent.

Dersom man utsetter de ved filtrering oppnådde krystallene for et høyvakuum (<1 torr), fjernes såvel organisk opp-løsningsmiddel som vann, spesielt i nærvær av et tørkemiddel, som for eksempel konsentrert svovelsyre, fosforsyreanhydrid, eller også etsekali eller etsenatron, samt silikagel. If the crystals obtained by filtration are exposed to a high vacuum (<1 torr), both organic solvent and water are removed, especially in the presence of a drying agent, such as concentrated sulfuric acid, phosphoric anhydride, or also caustic soda or caustic soda, as well as silica gel.

Stabilitetsundersøkelser gjennomført med de krystallinske saltene med formel II viser, sammenlignet med basen I, en vesentlig forbedring av stabiliteten. Stability studies carried out with the crystalline salts of formula II show, compared to the base I, a significant improvement in stability.

Forsøk på forskjellige dyrespesies har vist at saltene også resorberes utmerket enteralt. Tests on different animal species have shown that the salts are also absorbed excellently enterally.

Forbindelsene med generell formel II fremstilt ifølge oppfinnelsen administreres oralt i form av vanlige farmasøy-tiske preparater, som for eksempel kapsler, tabletter, pulvere, siruper eller suspensjoner. Dosen avhenger av alder, symptom og kroppsvekt for pasienten, samt behand-lingens varighet. Den ligger imidlertid som regel mellom 0,2 g og 5 g daglig, fortrinnvis mellom 0,5 g og 3 g daglig. Forbindelsene administreres fortrinnvis i oppdelte doser, eksempelvis to til fire ganger daglig, hvorved enkeltdosen eksempelvis kan inneholde mellom 50 og 500 mg virksomt stoff. The compounds of general formula II prepared according to the invention are administered orally in the form of usual pharmaceutical preparations, such as capsules, tablets, powders, syrups or suspensions. The dose depends on the age, symptoms and body weight of the patient, as well as the duration of the treatment. However, it is usually between 0.2 g and 5 g daily, preferably between 0.5 g and 3 g daily. The compounds are preferably administered in divided doses, for example two to four times a day, whereby the single dose can for example contain between 50 and 500 mg of active substance.

De orale preparatene kan inneholde de vanlige bærestoffene og/eller fortynningsmidlene. Følgelig kommer eksempelvis for kapsler eller tabletter bindemidler i betraktning som for eksempel gelatin, sorbitol, polyvinylpyrrolidon eller karboksymetylcellulose, fortynningsmidler, som for eksempel laktose, sukker, stivelse, kalsiumfosfat eller polyetylen-glykol, glidestoffer, som for eksempel talkum eller mag-nesiumstearat, for flytende preparater for eksempel vandige eller oljeformige suspensjoner, siruper eller lignende kjente preparatformer. The oral preparations may contain the usual carriers and/or diluents. Consequently, for example, for capsules or tablets binders come into consideration such as gelatin, sorbitol, polyvinylpyrrolidone or carboxymethyl cellulose, diluents, such as lactose, sugar, starch, calcium phosphate or polyethylene glycol, lubricants, such as talc or magnesium stearate, for liquid preparations, for example aqueous or oily suspensions, syrups or similar known forms of preparation.

De følgende utførelseseksemplene på ifølge oppfinnelsen fremstillbare salter av forbindelsen med formelen I, 7-[2-(2-aminotiazol-4-yl )-2-(Z)-hydroksyimino-acetamido]-3-metoksy-metyl-3-cef em-4 -karboksyl syr e-a-(2 ,2-dimetylpropanoyloksy )-etylester, tjener som ytterligere belysning av oppfinnelsen. The following embodiments of salts of the compound of the formula I that can be prepared according to the invention, 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxy-methyl-3-cef -4-carboxylic acid e-a-(2,2-dimethylpropanoyloxy)-ethyl ester, serves as further elucidation of the invention.

UTFØRELSESEKSEMPLER EXECUTION EXAMPLES

Utførelseseksempel 1 Execution example 1

7 - [2 - ( 2-aminotiazol-4-yl)-2-(Z)-hydroksyimino-acetamidol] -3-met ok syrne tyl - 3- cef em-4-karboksyl syre-S-( 2 ,2-dime tyl-propanoyloksy)-etylester-benzensulfonat 7 - [2 - ( 2-Aminothiazol-4-yl)-2-(Z)-Hydroxyimino-acetamidol] -3-met ok acid tyl - 3- cef em-4-carboxylic acid-S-( 2 ,2- dimethyl-propanoyloxy)-ethyl ester-benzenesulfonate

Til en oppløsning av 1,5 g (2,77 mmol) 7-[2-(2-aminotiazol-4-y1 ) -2 - ( Z )-hydroksyimino-acetamido]-3-metoksymetyl-3-cefem-4-karboksyl-a-(2,2-dimetyl-propanoyloksy)-etylester i 21 ml eddikester "ble det dråpevis tilsatt en oppløsning av 0,44 g (1 ekvivalent) benzensulfonsyre i 9 ml eddikester. Etter begynnende krystallisasjon ble det omrørt i 30 minutter, frasuget og ettervasket med litt dietyleter. Etter tørking over CaClg/parafin i vakuum, ble det oppnådd 1,4 g av den ønskede forbindelsen i overskriften, som kunne identifiseres under polarisasjonsmikroskop som krystallinsk materiale og som ifølge HPLC besto av en tilnærmet l:l-blanding av de to diastereomerene. To a solution of 1.5 g (2.77 mmol) 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4- carboxyl-α-(2,2-dimethyl-propanoyloxy)-ethyl ester in 21 ml of acetic ester "a solution of 0.44 g (1 equivalent) of benzenesulfonic acid in 9 ml of acetic ester was added dropwise. After initial crystallization, it was stirred for 30 minutes , sucked off and washed with a little diethyl ether. After drying over CaClg/paraffin in vacuo, 1.4 g of the desired compound in the title was obtained, which could be identified under a polarizing microscope as crystalline material and which, according to HPLC, consisted of an approximately l:l - mixture of the two diastereomers.

Frysepunkt: fra 198°C (under dekomponering) Freezing point: from 198°C (during decomposition)

ljj-KTMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9E, 2 x s, tert.-butyl), 1.48 (1H, dd, CH(CH3)), 3.2 (3E, 2 x s, 0CH3), 3.47-3.7 (2E, 2 x dd, S-CH2), 4.13 (2E, bs, 3'-CE2), 5,21 (1E, 2 x d, J = 6Ez, 6-Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 7-E), 6.8 (1E, 2 x s, tiazol-E), 6.9 (1E, dq, CE-CE3), 7.3 (3E, m, arom. E), 7.6 (2E, m, arom. E), 9.65 (1E, d, NE), 12.05 (1E, bs, oksim-E). ljj-KTMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9E, 2 x s, tert.-butyl), 1.48 (1H, dd, CH(CH3)), 3.2 (3E, 2 x s, 0CH3 ), 3.47-3.7 (2E, 2 x dd, S-CH2), 4.13 (2E, bs, 3'-CE2), 5.21 (1E, 2 x d, J = 6Ez, 6-Ez, 6-E) , 5.83 (1E, 2 x dd, J = 6Ez, 7-E), 6.8 (1E, 2 x s, thiazole-E), 6.9 (1E, dq, CE-CE3), 7.3 (3E, m, arom. E ), 7.6 (2E, m, arom. E), 9.65 (1E, d, NE), 12.05 (1E, bs, oxime-E).

Elementanalyse Element analysis

C27<H>32<N>5°11S3 beregnet C 46.3 E 4.8 N 10.0 0 25.1 S 13.8 C27<H>32<N>5°11S3 calculated C 46.3 E 4.8 N 10.0 0 25.1 S 13.8

(699.78) funnet C46.3 E 4.8 N 10.1 0 25.3 S 13.5 (699.78) found C46.3 E 4.8 N 10.1 0 25.3 S 13.5

TJtførelseseksempel 2 Implementation example 2

7-[2-(2-aminotiazol-4-yl )-2 -(Z )-hydroksyimino-acetamido] -3-me tok syrne tyl -3-cef em-4-karboksyl syr e-a-(2 ,2-dimetyl-propanoyloksy )-etylester-toluensulfonat 7-[2-(2-Aminothiazol-4-yl)-2-(Z)-Hydroxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid e-a-(2,2-dimethyl -propanoyloxy)-ethyl ester toluenesulfonate

Til en oppløsning av 1,08 g (2 mmol) 7-[2-2-aminotiazol-4-yl ) - 2 - ( Z )-hydroksyimino-acetamido]-3-metoksymetyl-3-cefem-4-karboksylsyre-a-(2,2.dimetyl-propanoyloksy)-etylester i 3 ml aceton ble det tilsatt en oppløsning av 570 mg (3 mmol) p-toluensulfonsyre i 1 ml aceton. Deretter ble det til den raskt dannende krystallsuspensjonen under omrøring langsomt og dråpevis tilsatt 28 ml vann. Deretter ble det krystallinske bunnfallet frasuget, vasket åtte ganger med 3 ml vann og tørket i vakuum over kalsiumklorid/parafin. Man fikk To a solution of 1.08 g (2 mmol) 7-[2-2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid-a -(2,2.dimethyl-propanoyloxy)-ethyl ester in 3 ml of acetone, a solution of 570 mg (3 mmol) of p-toluenesulfonic acid in 1 ml of acetone was added. Then, 28 ml of water was slowly and dropwise added to the rapidly forming crystal suspension while stirring. The crystalline precipitate was then suctioned off, washed eight times with 3 ml of water and dried in vacuum over calcium chloride/paraffin. One got

1,08 g av den ønskede forbindelsen i overskriften som ifølge HPLC besto av en tilnærmet l:l-blanding av diastereomerene og ble karakterisert som krystallinsk under polarisasjonsmikroskop. 1.08 g of the desired title compound which, according to HPLC, consisted of an approximately 1:1 mixture of the diastereomers and was characterized as crystalline under a polarizing microscope.

Frysepunkt: fra 190°C (under dekomponering) Freezing point: from 190°C (during decomposition)

ljj-NMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9E, 2 x s, tert.-butyl), 1.47 (1H, dd, CH-CH3), 2.3 (3E, s, CE3 i aromat), 3.2 (3E, 2 x s,0CE3), 3.47 - 3.7 (2E, 2 x dd, S-CE2), 4.13 (2E, bs, CE2-0CE3), 5.23 (1E, 2 x d, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 7-E), 6.83 (1E, 2 x s, tiazol-E), 6.9 (1E, dq, CE-CE3), 7.1 og 7.5 (4E, d, arom. E), 9.68 (1E, d, NE), 12.08 (1E, b, oksim-E). ljj-NMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9E, 2 x s, tert.-butyl), 1.47 (1H, dd, CH-CH3), 2.3 (3E, s, CE3 in aromatic ), 3.2 (3E, 2 x s,0CE3), 3.47 - 3.7 (2E, 2 x dd, S-CE2), 4.13 (2E, bs, CE2-0CE3), 5.23 (1E, 2 x d, J = 6Ez, 6 -E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 7-E), 6.83 (1E, 2 x s, thiazole-E), 6.9 (1E, dq, CE-CE3), 7.1 and 7.5 (4E, d, arom. E), 9.68 (1E, d, NE), 12.08 (1E, b, oxime-E).

Elementanalyse Element analysis

<c>28<E>36N<2>5°11S3 beregnet C 47,1 E 4,9 N 9,8 0 24,7 S 13,5 <c>28<E>36N<2>5°11S3 calculated C 47.1 E 4.9 N 9.8 0 24.7 S 13.5

(713,80) funnet C 47,4 E 4,9 N 10,0 0 24,4 S 13,1 (713.80) found C 47.4 E 4.9 N 10.0 0 24.4 S 13.1

Utførelseseksempel 3 Execution example 3

7-[2-(2-aminotiazol-4-yl )-2-(Z )-hydroksyimino-acetamido]-3-me tok syrne ty 1 - 3-cef em-4-karboksyl syr e-a- (2 ,2-dimetylpropanoyloksy)-etylester-p-etylbenzensulf onat 7-[2-(2-aminothiazol-4-yl )-2-(Z )-hydroxyimino-acetamido]-3-me toc acid ty 1 - 3-cef em-4-carboxylic acid e-a-(2 ,2- dimethylpropanoyloxy)-ethyl ester-p-ethylbenzenesulfonate

Til en oppløsning av 1,08 g (2 mmol) 7-[2-(2-aminotiazol-4-y1 ) - 2 - ( Z)-hydroksyimino-acetamido]-3-metoksymetyl-3-cefem-4-karboksylsyre-a-(2,2.dimetylpropanoyloksy)-etylester i 3 ml aceton ble det tilsatt en oppløsning av 664 mg p-etylben-zensulfonsyre (3 mmol) i 1 ml aceton og deretter langsomt, under omrøring, 28 ml vann. Etter fullført tilsats ble det podet og omrørt i 15 minutter. Det krystallinske bunnfallet ble frasuget, vasket åtte ganger, hver gang med 3 ml vann og tørket i vakuum og kalsiumklorid/parafin. Man fikk 1,28 g av den ønskede forbindelsen i overskriften som ifølge HPLC besto av en tilnærmet l:l-blanding av de to diastereomerene og som under polarisasjonsmikroskop ble karakterisert som krystallinsk. To a solution of 1.08 g (2 mmol) 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid- α-(2,2.Dimethylpropanoyloxy)-ethyl ester in 3 ml of acetone, a solution of 664 mg of p-ethylbenzenesulfonic acid (3 mmol) in 1 ml of acetone was added and then slowly, with stirring, 28 ml of water. After the addition was complete, it was inoculated and stirred for 15 minutes. The crystalline precipitate was filtered off with suction, washed eight times, each time with 3 ml of water and dried in vacuo and calcium chloride/paraffin. 1.28 g of the desired compound in the title was obtained which, according to HPLC, consisted of an approximately 1:1 mixture of the two diastereomers and which was characterized as crystalline under a polarizing microscope.

Frysepunkt: fra 170°C (under dekomponering) Freezing point: from 170°C (during decomposition)

<I>jj-NMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9H, 2 x s, tert.-butyl), 1.17 (3E, t, CE3CE2-), 1.5 (3E, dd, CE-CE3), 2.6 (2E, q, CE3CE2-), 3.2 (3E, 2 x s, 0CE3) , 3.47 - 3.7 (2E, 2 x dd, S-CE2), 4.13 (2E, d, CE20CE3), 5.23 (1E, 2 x d, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 7-E), 6.83 (1E, 2 x s, tiazol-E), 6.9 (1E, dg, CE-CE3), 7.15 og 7.51 (4E, d, arom, E), 9.67 (1E, d, NE), 12.05 (1E, bs, oksim-E). <I>jj-NMR (270 MHz, DMS0-d6) : S (ppm) = 1.15 (9H, 2 x s, tert.-butyl), 1.17 (3E, t, CE3CE2-), 1.5 (3E, dd, CE -CE3), 2.6 (2E, q, CE3CE2-), 3.2 (3E, 2 x s, 0CE3) , 3.47 - 3.7 (2E, 2 x dd, S-CE2), 4.13 (2E, d, CE20CE3), 5.23 ( 1E, 2 x d, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 (1E, 2 x dd, J = 6Ez, 6-E), 5.83 ( 1E, 2 x dd, J = 6Ez, 7-E), 6.83 (1E, 2 x s, thiazole-E), 6.9 (1E, dg, CE-CE3), 7.15 and 7.51 (4E, d, arom, E) , 9.67 (1E, d, NE), 12.05 (1E, bs, oxime-E).

Elementanalyse Element analysis

<C>29<H>37<N>5°11S3 beregnet: C 47,9 E 5,1 N 9,6 0 24,2 S 13,2 <C>29<H>37<N>5°11S3 calculated: C 47.9 E 5.1 N 9.6 0 24.2 S 13.2

(727,86) funnet : C 47,6 E 5,2 N 9,8 0 24,0 S 13,3 (727.86) found : C 47.6 E 5.2 N 9.8 0 24.0 S 13.3

Utførelseseksempel 4 Execution example 4

7-[2-(2-aminotiazol-4-yl )-2-(Z )-hydroksyimino-acetamido] -3-me tok syrne tyl -3- cef em-4-karboksyl syr e-a-(2 ,2-dimetyl-propanoyloksy) etylester-toluensulfonat 7-[2-(2-Aminothiazol-4-yl)-2-(Z)-Hydroxyimino-acetamido]-3-methyl-3-cephem-4-carboxylic acid e-a-(2,2-dimethyl -propanoyloxy) ethyl ester toluenesulfonate

Til en oppløsning av 5 g (9,3 mmol) 7-[2-(2-aminotiazol-4-yl ) -2- ( Z )-hydroksyimino-acetamido]-3-metoksymetyl-3-cefem-4-karboksylsyre-a-(2,2-dimetyl-propanolyoksy) etylester i 32 ml etanol ble det dråpevis tilsatt en oppløsning på 2,1 g (11 mmol) p-toluensulfonsyre i 5 ml etanol. Etter 30 minutters omrøring ved romtemperatur, ble det til den dannede krystall-grøten totalt tilsatt 280 ml diisopropyleter og det ble omrørt omhyggelig. Deretter ble det dannede bunnfallet frasuget, vasket med litt diisopropyleter og resten tørket i vakuum over kalsiumklorid/parafin. Det ble oppnådd 5,4 g av den ønskede krystallinske forbindelsen i overskriften som ifølge HPLC besto av en tilnærmet l:l-blanding av de to diastereomerene og som når det gjelder fysikalske og kjemiske egenskaper, var identisk med produktet fra utførelseseksempel 2. To a solution of 5 g (9.3 mmol) 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid- α-(2,2-dimethyl-propanolyloxy) ethyl ester in 32 ml of ethanol, a solution of 2.1 g (11 mmol) of p-toluenesulfonic acid in 5 ml of ethanol was added dropwise. After stirring for 30 minutes at room temperature, a total of 280 ml of diisopropyl ether was added to the formed crystal slurry and it was stirred carefully. The precipitate formed was then suctioned off, washed with a little diisopropyl ether and the residue dried in vacuum over calcium chloride/paraffin. 5.4 g of the desired crystalline compound in the title was obtained which, according to HPLC, consisted of an approximately 1:1 mixture of the two diastereomers and which, in terms of physical and chemical properties, was identical to the product from embodiment 2.

Frysepunkt: fra 190°C (under dekomponering) Freezing point: from 190°C (during decomposition)

Utførelseseksempel 5 Execution example 5

7-[2-(2-aminotiazol-4-yl )-2-(Z )-hydroksyimino-acetamido] - 3-metoksyrne tyl-3-cefem-karboksylsyre-a-(2,2-dimetyl-propanoyloksy) etylester-toluensulfonat 7-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido]-3-methoxyethyl-3-cephem-carboxylic acid-α-(2,2-dimethyl-propanoyloxy) ethyl ester- toluenesulfonate

Til en oppløsning av 5 g (9,3 mmol) 7-[2-aminotiazol-4-yl)-2-(Z )-hydroksyimino-acetamido] - 3 - me tok syrne tyl -3-cef em-4-karboksylsyre-cx-(2 ,2-dimetyl-propanoyloksy) etylester i 35 ml aceton ble det dråpevis tilsatt en oppløsning av 1,8 g (15 mmol) p-toluensulfonsyre i 5 ml aceton. Etter kort omrøring dannet det seg et tykt bunnfall. Etter 15 minutters omrøring ble det for fullstendiggjørelse av krystallisasjonen langsomt tilsatt totalt 185 ml diisopropyleter og omrørt i kort tid. Deretter frasugde man bunnfallet, vasket med litt diisopropyleter og tørket i vakuum over kalsiumklorid/parafin. Man fikk 5,9 g krystallinsk tittelforbindelse som ifølge HPLC besto av en tilnærmet l:l-blanding av de to diastereomerene og som når det gjelder fysikalske og kjemiske egenskaper var identisk med produktet fra utførelseseksempel 2. To a solution of 5 g (9.3 mmol) of 7-[2-aminothiazol-4-yl)-2-(Z )-hydroxyimino-acetamido]-3-me, the acid ethyl-3-cephem-4-carboxylic acid -cx-(2,2-dimethyl-propanoyloxy) ethyl ester in 35 ml of acetone, a solution of 1.8 g (15 mmol) of p-toluenesulfonic acid in 5 ml of acetone was added dropwise. After brief stirring, a thick precipitate formed. After 15 minutes of stirring, to complete the crystallization, a total of 185 ml of diisopropyl ether was slowly added and stirred for a short time. The precipitate was then suctioned off, washed with a little diisopropyl ether and dried in vacuum over calcium chloride/paraffin. 5.9 g of the crystalline title compound was obtained which, according to HPLC, consisted of an approximately 1:1 mixture of the two diastereomers and which, in terms of physical and chemical properties, was identical to the product from embodiment 2.

Frysepunkt: fra 190°C (under dekomponering) "Utførelseseksempel 6 Freezing point: from 190°C (during decomposition) "Embodiment example 6

7-2-(2-aminotiazol-4-yl)-2-(Z)-hydroksyimino-acetamido-3-me tok syrne tyl -3-cef em-4-karboksyl syr e-a-(2 ,2-dimetyl-propanoyloksy) etylester-toluensulfonat 7-2-(2-Aminothiazol-4-yl)-2-(Z)-Hydroxyimino-acetamido-3-methyl-3-cef em-4-carboxylic acid e-a-(2,2-dimethyl-propanoyloxy) ) ethyl ester toluenesulfonate

Til en oppløsning av 5 g (9,3 mmol) 7-2-(2-aminotiazol-4-yl ) - 2- ( Z ) -hydroksyimino-acetamido-3-metoksymetyl-3-cefem-4-karboksylsyre-a-(2,2-dimetyl-propanoyloksy)-etylester i 35 ml aceton ble det dråpevis tilsatt en oppløsning av 2,1 g (11 mmol) p-toluensulfonsyre i 5 ml aceton. Etter kort omrøring dannet det seg et bunnfall som var ferdigutfelt etter langsom tilsats av 250 ml t-butylmetyleter. Etter 15 minutters etteromrøring, ble de krytallinske produkter frasuget, vasket med litt t-butylmetyleter og tørket i vakuum over kalsiumklorid/paraf in. Man fikk 4,6 g av den ønskede krystallinske forbindelsen i overskriften som ifølge HPLC besto av en tilnærmet l:l-blanding av de to diastereomerene, og som når det gjelder fysikalske og kjemiske egenskaper var identisk med produktet fra utførelseseksempel 2. To a solution of 5 g (9.3 mmol) 7-2-(2-aminothiazol-4-yl)-2-(Z)-hydroxyimino-acetamido-3-methoxymethyl-3-cephem-4-carboxylic acid-α- (2,2-dimethyl-propanoyloxy)-ethyl ester in 35 ml of acetone, a solution of 2.1 g (11 mmol) of p-toluenesulfonic acid in 5 ml of acetone was added dropwise. After brief stirring, a precipitate formed which was completely precipitated after the slow addition of 250 ml of t-butyl methyl ether. After 15 minutes of post-stirring, the crystalline products were suctioned off, washed with a little t-butyl methyl ether and dried in vacuum over calcium chloride/paraffin. 4.6 g of the desired crystalline compound in the title was obtained which, according to HPLC, consisted of an approximately 1:1 mixture of the two diastereomers, and which in terms of physical and chemical properties was identical to the product from embodiment 2.

Frysepunkt: fra 190°C (under dekomponering) Freezing point: from 190°C (during decomposition)

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive krystallinske cefemsyreaddisjonssalter med generell formel II hvori R betyr hydrogen eller C^-C^alkyl og gruppen =N-OH står i syn-posisjon, karakterisert ved at man omsetter et amorft cefem med generell formel I med en syre med generell formel III hvori R står for hydrogen eller C-^-C^alkyl, i et organisk oppløsningsmiddel og lar syreaddisjonssalt krystalliseres direkte eller ved tilsats av et annet organisk oppløsnings-middel eller av vann.Analogous process for the preparation of therapeutically active crystalline cephem acid addition salts of general formula II in which R means hydrogen or C^-C^alkyl and the group =N-OH is in the syn position, characterized by reacting an amorphous cephem of general formula I with an acid with general formula III in which R stands for hydrogen or C-^-C^alkyl, in an organic solvent and allows the acid addition salt to be crystallized directly or by the addition of another organic solvent or of water.
NO902607A 1989-06-13 1990-06-12 Analogous Process for the Preparation of Therapeutically Active Crystalline Cephemic Acid Salts NO174258C (en)

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